Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits
Open accessAbstract
In this review we describe how highly addictive psychostimulants such as cocaine and methamphetamine actions might underlie hypoexcitabilty in frontal cortical areas observed in clinical and preclinical models of psychostimulant abuse. We discuss new mechanisms that describe how increments on synaptic dopamine release are linked to reduce calcium influx in both pre and postsynaptic compartments on medial PFC networks, therefore modulating synaptic integration and information. Sustained DA neuromodulation by addictive psychostimulants can "lock" frontal cortical networks in deficient states. On the other hand, other psychostimulants such as modafinil and methylphenidate are considered pharmacological neuroenhancement agents that are popular among healthy people seeking neuroenhancement. More clinical and preclinical research is needed to further clarify mechanisms of actions and physiological effects of cognitive enhancers which show an opposite pattern compared to chronic effect of addictive psychostimulants: they appear to increase cortical excitability. In conclusion, studies summarized here suggest that there is frontal cortex hypoactivity and deficient inhibitory control in drug-addicted individuals. Thus, additional research on physiological effects of cognitive enhancers like modafinil and methylphenidate seems necessary in order to expand current knowledge on mechanisms behind their therapeutic role in the treatment of addiction and other neuropsychiatric disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A dramatic increase in DA in the nucleus accumbens is related to severe abuse and addiction.
“In addition, the dramatic increase in DA in the nucleus accumbens (NAc), a key brain region responding to reward (13, 14), is also related to severe abuse and addiction.”
From Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine (2022) · cites this paper as [13]
Section 4, “Dopamine and motivational salience” (page unavailable), describes increased dopamine release in the nucleus accumbens and says addictive drugs can enhance dopamine transmission and act as reinforcers. Section 5 links dopamine-system responses to the development of addiction. Neither passage specifically links a dramatic increase in nucleus accumbens dopamine to severe abuse or addiction. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?
Berridge, K. C., & Robinson, T. E. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00019-8 · Cited by 4,127 · see citing works
Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications
Goldstein, R. Z., & Volkow, N. D. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3119 · Cited by 2,749 · see citing works
Multiple dopamine functions at different time courses
Schultz, W. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.061604.135722 · Cited by 1,415 · see citing works
Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V., & Arnsten, A. F. T. (2007) · Nature Neuroscience · doi:10.1038/nn1846 · Cited by 1,013 · see citing works
Kooij, S. J., Bejerot, S., Blackwell, A., Caci, H., Casas-Brugué, M., Carpentier, P. J., Edvinsson, D., Fayyad, J., Foeken, K., Fitzgerald, M., et al. (2010) · BMC Psychiatry · doi:10.1186/1471-244x-10-67 · Cited by 928 · see citing works
Wang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., Duque, A., Vijayraghavan, S., Brennan, A., Dudley, A., Nou, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.015 · Cited by 672 · see citing works
Kuczenski, R., & Segal, D. S. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68052032.x · Cited by 623 · see citing works
Berridge, C. W., Devilbiss, D. M., Andrzejewski, M. E., Arnsten, A. F. T., Kelley, A. E., Schmeichel, B., Hamilton, C., & Spencer, R. C. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.04.022 · Cited by 617 · see citing works
Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons
Magee, J. C. (1999) · Nature Neuroscience · doi:10.1038/9158 · Cited by 617 · see citing works
Addiction circuitry in the human brain
Volkow, N. D., Wang, G.-J., Fowler, J. S., & Tomasi, D. (2012) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134625 · Cited by 592 · see citing works
Monterosso, J. R., Ainslie, G., Xu, J., Cordova, X., Domier, C. P., & London, E. D. (2007) · Human Brain Mapping · doi:10.1002/hbm.20281 · Cited by 335 · see citing works
Gorelova, N., Seamans, J. K., & Yang, C. R. (2002) · Journal of Neurophysiology · doi:10.1152/jn.00335.2002 · Cited by 302 · see citing works
Paulus, M. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00334-7 · Cited by 283 · see citing works
Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits
Gao, W.-J., Krimer, L. S., & Goldman-Rakic, P. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.1.295 · Cited by 257 · see citing works
Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers
Johanson, C.-E., Frey, K. A., Lundahl, L. H., Keenan, P., Lockhart, N., Roll, J., Galloway, G. P., Koeppe, R. A., Kilbourn, M. R., Robbins, T., et al. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0330-6 · Cited by 233 · see citing works
Stimulant Medication and Substance Use Outcomes
Humphreys, K. L., Eng, T., & Lee, S. S. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.1273 · Cited by 211 · see citing works
Dalsgaard, S., Mortensen, P. B., Frydenberg, M., & Thomsen, P. H. (2014) · Addictive Behaviors · doi:10.1016/j.addbeh.2013.09.002 · Cited by 144 · see citing works
Markowitz, J. S., DeVane, C. L., Pestreich, L. K., Patrick, K. S., & Muniz, R. (2006) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2006.16.687 · Cited by 109 · see citing works
Methylphenidate Increases Cortical Excitability via Activation of Alpha-2 Noradrenergic Receptors
Andrews, G. D., & Lavin, A. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300818 · Cited by 101 · see citing works
Flagged first, then by citations
Research works printed but not linked: 18
- D. Repantis, P. Schlattmann, O. Laisney, I. Heuser, Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review, Pharmacol. Res. 62 (3) (2010) 187-206.
- R.M. Battleday, A.K. Brem, Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review, Eur. Neuropsychopharmacol. 25 (11) (2015) 1865-1881.
- M.J. Minzenberg, C.S. Carter, Modafinil: a review of neurochemical actions and effects on cognition, Neuropsychopharmacology 33 (7) (2008) 1477-1502.
- F.J. Urbano, E. Leznik, R.R. Llinás, Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling, Proc. Natl. Acad. Sci. U. S. A 104 (2007) 12554-12559.
- J.P. Lindenmayer, H. Nasrallah, M. Pucci, S. James, L. Citrome, A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities, Schizophr. Res. 147 (2-3) (2013) 241-252.
- C. Andrade, S. Kisely, I. Monteiro, S. Rao, Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials, J. Psychiatr. Res. 60 (2015) 14-21.
- D. Sulzer, M.S. Sonders, N.W. Poulsen, A. Galli, Mechanisms of neurotransmitter release by amphetamines: a review, Prog. Neurobiol. 75 (6) (2005) 406-433.
- G. Di Chiara, A. Imperato, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Natl. Acad. Sci. U. S. A. 85 (14) (1988) 5274-5278.
- M.E. Rice, J.C. Patel, Somatodendritic dopamine release: recent mechanistic insights, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 370 (1672) (2015), pii: 20140185.
- A.J. Rashid, C.H. So, M.M. Kong, T. Furtak, M. El-Ghundi, R. Cheng, B.F. O'Dowd, S.R. George, D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum, Proc. Natl. Acad. Sci. U. S. A. 104 (2) (2007) 654-659.
- M. Bentivoglio, M. Morelli, The organization and circuits of mesencephalic dopaminergic neurons and the distribution of dopamine receptors in the brain, in: S.B. Dunnett, M. Bentivoglio, A. Bjorklund, T. Hokfelt (Eds.), Dopamine, Elsevier, San Diego, CA, 2005, pp. 1-107.
- J.K. Seamans, D. Durstewitz, B.R. Christie, C.F. Stevens, T.J. Sejnowski, Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 301-306.
- P.S. Goldman-Rakic, C. Leranth, S.M. Williams, N. Mons, M. Geffard, Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex, Proc. Natl. Acad. Sci. U.S.A. 86 (22) (1989) 9015-9019.
- J.K. Seamans, D. Durstewitz, B.R. Christie, C.F. Stevens, T.J. Sejnowski, Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 301-306.
- Y.Y. Huang, E. Simpson, C. Kellendonk, E.R. Kandel, Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors, Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 3236-3241.
- M.J. Minzenberg, C.S. Carter, Modafinil: a review of neurochemical actions and effects on cognition, Neuropsychopharmacology 33 (7) (2008) 1477-1502.
- B. González, C. Rivero-Echeto, J.L. Mu ñiz, F.J. García-Rill, V. Bisagno, Methamphetamine blunts Ca 2+ currents and excitatory synaptic transmission through D1 /5 receptor-mediated mechanisms in the mouse medial prefrontal cortex, Addict. Biol. (2015) (in press).
- K.M. Dürsteler, E.M. Berger, J. Strasser, C. Caflisch, J. Mutschler, M. Herdener, M. Vogel, Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence, Subst. Abuse Rehabil. (2016) (in press).
Cited by
Sorted by citations
Addiction, cognitive decline and therapy: Seeking ways to escape a vicious cycle
Perry, C. J., & Lawrence, A. J. (2017) · Genes, Brain and Behavior · doi:10.1111/gbb.12325 · Cited by 60 · see citing works
Pozzi, M., Carnovale, C., Peeters, G. G. A. M., Gentili, M., Antoniazzi, S., Radice, S., Clementi, E., & Nobile, M. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.05.021 · Cited by 56 · see citing works
Jian-min, C., Zhi-yuan, W., Shi-xuan, W., Rui, S., Ning, W., & Jin, L. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.885574 · Cited by 7 · see citing works
“In addition, the dramatic increase in DA in the nucleus accumbens (NAc), a key brain region responding to reward (13, 14), is also related to severe abuse and addiction.”
Background
- Authors
- Bisagno, V., González, B., & Urbano, F. J.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 109
- Pages
- 108-118
- ISSN
- 1043-6618 (ISSN-L)
- OpenAlex
- W2283194507
- Cited by
- 59
- References
- 19
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Research (publishedVersion)
- PubMed (publishedVersion)
- Conicet (submittedVersion, cc-by-nc-nd)
- Funders
- Agencia Nacional de Promoción Científica y Tecnológica (PICT-2012, BID 1728 OC/AR, PICT2014, UBACYT 2014-2017, PICT-2012-0924, 20120130101305BA, BID 1728 OC.AR.PICT, PICT-2014-2499)
- Secretaría de Ciencia y Técnica, Universidad de Buenos Aires (2014–2017, 20120130101305BA)
- Fondo para la Investigación Científica y Tecnológica (PICT‐2012‐1769, BID 1728, PICT 2014, 2014-2017, PICT 2012)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neuroethics, Human Enhancement, Biomedical Innovations
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- nootropic drugs, dopamine, prefrontal cortex, cocaine, methamphetamine, modafinil, methylphenidate, inhibitory control, addiction treatment, neuromodulation
- MeSH terms
- Modafinil, Central Nervous System Stimulants, Animals, Benzhydryl Compounds, Cocaine, Dopamine, Humans, Methamphetamine, Methylphenidate, Prefrontal Cortex, Nootropic Agents, Substance-Related Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
